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Axonal loss and demyelation in multiple sclerosis
  1. Centre for Functional Magnetic Resonance Imaging of the Brain, Department of Clinical Neurology, University of Oxford, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, UK

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    In the paper by Davie et al in this issue (pp710–715),1 proton magnetic resonance spectroscopy and magnetisation transfer imaging were combined in a study of 18 patients with multiple sclerosis to determine whether the axonal loss in lesions of multiple sclerosis is correlated with the extent of demyelination.

    Axonal damage is now often discussed as a likely cause of chronic disability in multiple sclerosis.2 3 But what is the cause of the axonal damage itself? It is tempting to speculate that it arises from injury secondary to a primary inflammatory response against myelin, but axonal injury in primary progressive multiple sclerosis occurs with relatively little demyelination. There is considerable heterogeneity of pathology in multiple sclerosis.4 It is possible that different mechanisms predominate in different patients (or perhaps at different stages of the disease). Central to understanding mechanisms of damage is to understand whether axonal damage occurs in parallel with demyelination.

    Magnetic resonance imaging can be used as a non-invasive probe of the pathology of multiple sclerosis as well as a clinical diagnostic tool. Although conventional MRI is relatively non-specific in the pathological information provided, newer techniques provide more specific information. Magnetisation transfer (MT) imaging generates contrast dependent on the association of brain water with macromolecular proteins particularly in myelin.4 It is a sensitive marker of demyelination in animal models. One useful contribution of Davie et al 1 is to give evidence that this is true in humans as well with the demonstration that reversible MT ratio changes occur with the reversible demyelinating pathology associated with central pontine myelinosis.

    Magnetic resonance spectroscopy allows measurement of relative concentrations of the acetylated amino acid N-acetylaspartate (NAA), a marker of axonal density and integrity in the brain.2Davie et al demonstrate that there is a significant correlation between the reduction in MT ratio and the reduction in NAA in the lesions of multiple sclerosis, particularly in patients with secondary progressive disease. This suggests a tight coupling between damage to myelin and damage to axons. The particularly strong correlation in patients with secondary progressive disease may be a consequence of the larger magnitude of changes in both perimeters in these patients rather than there being a fundamentally different mechanism in the operating in the patients with relapsing-remitting disease, although this cannot be clearly demonstrated with the data available. It is tempting to speculate that the extent of loss of NAA per unit change in the normalised MT ratio might be used to define the severity of damage in lesions and could be clinically predictive of progression of disease.

    Although the authors are rightly cautious in suggesting that their data allow strong inferences to be made regarding the mechanism of damage to axons, the results are consistent with the coupling of axonal injury and demyelination. Longitudinal studies of new lesions could provide more direct information relevant to the question of mechanism by defining the relative time course of changes. In emphasising the potential usefulness of integrating data from multiple new imaging methods to describe pathology of multiple sclerosis, Davie et al point the way forward for a whole new phase of imaging research in multiple sclerosis.


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